Purposes of suppositories

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1 Suppositories

2 Definition Are conical or ovoid, solid prep. For insertion into the body cavity where they melt,dissolve or disperse and exert a local or a systemic effect. Their basis is fat,a wax or glycerol-gelatin gelly. They weight 1,2 or occasionally 4 g.

3 Purposes of suppositories To exert a direct action on the rectum especially to relieve the pain and irritation of hemorrhoids and they contain: local anesthetic e.g. benzocaine Astringent e.g. Bismuth subgallate Anti-inflammatory agents e.g. hydrocortisone To promote evacuation of the bowel e.g. laxatives. To provide a systemic effect which is of particular value for : Patients who are unconscious, mentally disturbed or who cant administer drugs orally e.g. vomiting or fottreating infants and children or for Drugs destroyed or inactivated by the ph or enzymatic activity of the stomach or intestines,or to avoid entering the portal circulation after oral administration

4 Examples of drugs administered rectally in the form of suppositories for their systemic effects include (a) prochlorperazine and chlorpromazine for the relief of nausea and vomiting and as a tranquilizer; (b) oxymorphone HCl for opioid analgesia; (c) ergotamine tartrate for the relief of migraine syndrome; (d) indomethacin, a nonsteroidal anti-inflamatory analgesic and antipyretic; and

5 Some Factors that affect the Drug Absorption from rectal Suppositories 1. PHYSIOLOGIC FACTORS Colonic Content A drug will obviously have greater opportunity to make contact with the absorbing surface of the rectum and colon in an empty rectum. Therefore an evacuate enema may be administered and allowed to act before the administration of a suppository of a drug to be absorbed. Other conditions, such as diarrhea, colonic obstruction due to tumorous growths, and tissue dehydration can all influence the rate and degree of drug absorption from the rectum.

6 Circulation Route Drugs absorbed rectally, unlike those absorbed after oral administration, bypass the portal circulation to exert systemic effects. (The lower hemorrhoidal veins surrounding the colon receive the absorbed drug and initiate its circulation throughout the body, bypassing the liver. Lymphatic circulation also assists in the absorption of rectally administered drugs). ph and Lack of Buffering Capacity of the Rectal Fluids rectal fluids are essentially neutral in ph and have no effective buffer capacity, therefore the form in which the drug is administered will not be chemically changed by the environment.

7 2. PHYSIOCHEMICAL FACTORS OF THE DRUG AND SUPPOSITORY BASE Lipid Water Solubility The lipid water partition coefficient of a drug is an important consideration in the selection of the suppository base and in anticipating drug release from that base. A lipophilic drug that is distributed in a fatty suppository base in low concentration has less tendency to escape to the surrounding aqueous fluids than a hydrophilic substance in a fatty base. Particle Size The smaller the particle, the greater the surface area, the more readily the dissolution of the particle and the greater the chance for rapid absorption.

8 Nature of the Base The base must be capable of melting, softening, or dissolving to release its drug for absorption. If the base interacts with the drug it will inhibit its release and drug absorption will be impaired or even prevented. Also, if the base irritates the mucous membranes of the rectum, it may initiate a colonic response and prompt a bowel movement.

9 Properties of an ideal suppository base 1. Should be melt at body tempreture or dissolved or dispersed in body fluids. 2. Release any medication readily. 3. Keep its shape during handling. 4. Non toxic and non irritant to the mucous membrane. 5. Stable on storage. 6. Compatible with any added medication 7. Has wetting and emulsifying properties 8. Easily molded and not adhere to the mold. 9. Moldable by pouring or cold compression.

10 Types of suppository bases Fatty or oleaginous bases(natural or synthetic) Water-soluble or water-miscible bases. Miscellaneous bases, generally combinations of lipophilic and hydrophilic substances

11 Fatty or Oleaginous Bases Theobroma oil (cocoa butter) Advantages Has a melting point range of C. Readily liquefy on warming and rapid setting on cooling. Miscible with many ingredient.

12 Disadvantages Polymorphism: When melted and cooled it solidifies in different crystalline forms, depending on the temp. of the melting, rate of the cooling and size of the mass. Adherence to the mold Because Theobroma oil doesn t contract enough on cooling to loosen the suppository in the mold, sticking may occur.this is prevented by lubricating the mold before use. Softening point too low for hot climate To rise the softening point,white bees wax may be added to Theobroma oil suppository intended for use in tropical and subtropical countries.

13 This lowering in solidification point lead to sedimentation of suspended solids. is prone to oxidation (this can be overcome by storage in a cool dark place) poor water absorbing capacity This fault can be improved by the addition of emulsifying agent. leakage from the body Relatively high cost. Theobroma oil may vary in consistency,odor and color depending on its source like other natural products.

14 Synthetic fats It is used as substitute free from disadvantages of Theobroma oil. It was produced by hydrolyzing the vegetable oil then hydrogenating the free fatty acids and finally re-esterifying the acids by heating with glycerol.

15 They are superior to Theobroma oil because 1. Their solidifying points are unaffected by overheating. 2. Have good resistance to oxidation 3. Small difference bet. Melting and setting points (1.5-2)hence i. They set quickly ii. iii. The risk of sedimentation is low Easier to administer. When the setting point of a base is well below the melting point, the supp. Soften quickly when handled and become too slippery to administer. 4.. Its availability in a series of grades with slightly difference in Melting Point ranges and degree of hardness. 5. Has good water absorbing capacity because they usually contain a proportion of glycerides some of which are w/o E.A. 6. They produce supp. That is white and almost odorless and has very attractive, clean and polished appearance. 7-they contract significantly on cooling.

16 Disadvantages of synthetic fatty bases 1. They become brittle if cooled quickly, 0.05 % of polysorbate 80 help to correct this fault. 2. They are more fluid than theobroma oil when melted and at this stage sedimentation may occur. Thickeners such as Mg stearate,bentonite and colloidal silicon dioxide may be added to reduce this.

17 Water-Soluble and Water-Miscible 1. Glycero-gelatin Bases Is a mix. Of glycerol and water made into stiff jelly by adding gelatin. Contain about 14% w/w gelatin( 18% in hot climates) and 70% w/w glycerol. Glycero-gelatin dissolves in body secretions and therefore is preferable over the fatty base for administering antiseptics. Since solution is slow,drug release is more prolonged than from fatty bases. At present the B.P allows a maximum disintegration time of 1 hr for glycerol supp.

18 Glycero-gelatin base's disadvantages: 1. They have a physiological action (laxatives) 2. More difficult to prepare and handled. 3. are hygroscopic leading to dehydration of the rectal mucosa. 4. Their dissolution time depends on the content and quality of the gelatin and the age of the base

19 Synthetic water soluble base Macrogols Are a mixture of poly-condensation products of ethylene oxide and water and they are described by numbers representing their average molecular weight. They vary in consistency from viscous liq. To waxy solids Macrogols viscous liq greasy,semisolid waxy solids

20 Advantages : -Don t stick to the mold so, no lubricant is required -No leakage from the body due to the high viscosity of their solution after melt. - Have good water absorbing capacity -Have clean smooth appearance.

21 Disadvantages 1. They are hygroscopic 2. Retention of the drug in the liquefied base in the body with consequent reduction in therapeutic activity 3. Products sometimes fracture on storage. 4. Crystal growth which in addition to making the product brittle, the crystals may be irritating and take longer time to dissolve. 5. They are incompatible with bismuth salts,tannins and phenols leading to liquefaction of the supp.

22 Miscellaneous Bases In the miscellaneous group of bases are mixtures of oleaginous and water-soluble or water- miscible materials. These materials may be chemical or physical mixtures. Some are preformed emulsions, generally of the water-in-oil type, or they may be capable of dispersing in aqueous fluids.

23 PREPARATION OF SUPPOSITORIES Suppositories are prepared by three methods: 1. Molding from a melt, 2. Compression, and 3. Hand rolling and shaping. The method most frequently employed both on a small scale and on an industrial scale is molding.

congeal into suppositories, (e) removing the formed suppositories from the mold.

24 PREPARATION BY MOLDING The steps in molding include (a) melting the base, (b) incorporating any required medicaments, (c) pouring the melt into molds, (d) allowing the melt to cool and congeal into suppositories, (e) removing the formed suppositories from the mold. Cocoa butter, glycerinated gelatin, polyethylene glycol, and most other bases are suitable for preparation by molding.

25 Calibration of the Mold Each individual mold is capable of holding a specific volume of material in each of its openings. Because of the difference in the densities of the materials, if the base is cocoa butter, the weight of the suppositories will differ from the weight of suppositories prepared in the same mold with a base of polyethylene glycols. Similarly, any added medicinal agent alters the density of the base, and the weight of the resulting suppository differs from that of those prepared with base material alone.

26 The first step in calibration of a mold is to prepare molded suppositories from base material alone. After removal from the mold, the suppositories are weighed and the total weight and average weight of each suppository are recorded (for the particular base used).

27 Displacement value (DV) The number of parts by weight of the drug that displace one part by weight of the base. e.g.

28 Q: Calculate the DV for zinc oxide in the following batch Zinc oxide 40% Theobroma oil q.s. Mitt 6 supp. Mold 1 g If you know that weight of 1 supp. Containing the drug is 1.5 g Answer You should calculate for 6 supp. Wt. of six unmedicated supp.= 6g Wt of 6 medicated supp.= 9 g amount of Theobroma oil in 6 medicated supp. = 60/100 * 9 =5.4 g Amount of zinc oxide in 6 medicated supp.= 40/100*9 = 3.6 g Theobroma oil displaced by (3.6 g) of drug = 6 5.4= 0.6 g T.F. DV for zinc oxide = 3.6/0.6= 6

29 Q2:. If a prescription requires 400 mg of bismuth subgallate per suppository weighing 2 grams, what would be the displacement value if it is known That 6 suppositories with required bismuth subgallate weigh 13.6 g? Answer : Theoretical weight of six cocoa butter suppositories without bismuth subgallate = 12 g Given weight of six cocoa butter suppositories with bismuth subgallate = 13.6 g Amount of bismuth subgallate in the suppositories = = 2.4 g Amount of cocoa butter in the bismuth subgallate suppositories = = 11.2 g Cocoa butter displaced by 2.4 g of bismuth subgallate = = 0.8 The displacement value of bismuth subgallate is 2.4/0.8 = X/1, or X = 3

30 Q3 If 12 cocoa butter suppositories containing 40% zinc oxide weigh 17.6 grams, what is the displacement value of zinc oxide? Assume that the suppositories are made in a 1-g mold.

31 Answer Given weight of 12 suppositories with zinc oxide = 17.6 grams Weight of zinc oxide in the suppositories = (40/100) 17.6 = 7.04 g Weight of cocoa butter in the suppositories = (60/100) 17.6 = g Theoretical weight of 12 suppositories without zinc oxide = 12 g Cocoa butter displaced by 7.04 g of zinc oxide = = 1.44 Displacement value of zinc oxide = (7.04/1.44) = (X/1); X = 4.89

33 SPECIFIC PROBLEMS IN FORMULATING SUPPOSITORIES : 1- Water in suppositories: water as a solvent for drug should be avoided because water accelerates oxidation of fats and increase contamination with bacteria or fungi necessitates the addition of bacteriostatic agents (as parabens) Also water increase Reaction between ingredients.moreover,if water evaporates, the dissolved substance crystallizes out. 2- Hygroscopicity: a- Glycerinated gelatin suppositories lost moisture by evaporation in dry climates and absorbed moisture under conditions of high humidity b- PEG bases are also hygroscopic. 33

34 3- Incompatibilities: a- PEG bases are incompatible with tannic acid, aminopyrine, quinine, asprin, benzocaine & sulphonamides b- Many chemicals have a tendency to crystallize out of PEG, e.g salicylic acid & camphor. c- Fatty bases with significant hydroxyl values may react with acidic ingredients. 4- Viscosity: The viscosity of the melted suppository base and its behavior in the rectum after melting is important because low viscosity melted base associated with increase sedimentation of suspended particles. To overcome the problems of low viscosity bases: Cetyl, stearyl or or stearic acid are added to improve the consistency of suppositories or The inclusion of 2% aluminum monostearate increase the viscosity of the fat base and maintain homogenous suspension of insoluble material 34

35 5- Brittleness : Suppositories made from cocoa butter are elastic and don't fracture readily. Synthetic fat base with high degree of hydrogenation and a higher solids content at room temperature are usually more brittle. To overcome brittleness, Addition of small amount of castor oil, glycerin imparts plasticity to a fat 6- Volume contraction: Occurs in many melted suppository base after cooling the mold, result in: a- Good mold release (contraction facilitate the removal of the suppository from the mold, eliminating the need for mold release agents). b- Contraction hole formation at the open end of the mold 35

36 Lubricant or mold releasing agent: Cocoa butter adhere to suppository molds because of its low volume contraction. A various mold lubricants or release agents must be used to overcome this difficulty (mineral oil, aqueous solution of sodium lauryl sulfate, alcohol, silicones, soap). The release of suppository from damaged mold was improved by coating the cavities with polytetrofluoroethylene (Teflone). 36

37 7- Rancidity and Antioxidant: Rancidity results from the autoxidation and subsequent decomposition of unsaturated fats into aldehyde and ketones,or acids which have strong unpleasant odor. Example of effective antioxidant are phenols such as " hydroquinone 37

38 Quality Control of Suppository 1) Surface appearance and shape: absence of fissuring absence of migration of active ingredient, absence of pitting, absence of fat blooming (dullness of surface) 2) MELTING RANGE TEST: Macro-melting range: measures the time it takes for the entire suppository to melt when immersed in a constant temperature (37 C) water bath. Micro-melting range: is the melting range measured in capillary tubes for the fat base only. 38

39 3) LIQUIFACTION OR SOFTENING TIME TESTS OF RECTAL SUPPOSITORIES: The "softening test" measures the liquefaction time of rectal suppositories are an apparatus that simulate softening in-vitro conditions (at 37 C). 4) BREAKING TEST: It is designed as a method for measuring the fragility or brittleness of suppositories 39

40 5) Melting & solidification Solidification can be determine by using evacuated flask into which the melt is placed, the temp of cooling is noted to determine the solidification point. 40

41 PACKAGING OF SUPPOSITORY Suppository must be placed in a container in such a manner that they do not touch each other. Staining, breakage or deformation by melting caused by adhesion can result from poorly wrapped packaged suppository. Suppository is foiled in tin or Al paper and plastic. Over wrapping is done by hand or machine. Many suppositories are not individually, wrapped. In such cases, they are placed into cardboard boxes or plastic containers that have been molded to provide compartment for 6 or 12 suppositories. 41

42 IN- PACKAGE MOLDING: A significant advance in suppository manufacturing was the development of automated method for molding suppository, directly in their wrapping materials. This is currently accomplished with either plastic or Al-foil. *ADVANTAGE OF INPACKAGE MOLDING: 1. high production rate. 2. no generation of scraping. 3. no bulk handling. 4. maintenance of strict temperature control 42

43 STORAGE Suppository should be protected from heat, preferably stored in the refrigerator. Glycerinated gelatin suppositories should be protected from heat, moisture, and dry air by packaging in well-sealed containers and storing in a cool place. 43

Dr.N.Damodharan Professor and head Department of pharmaceutics SRM college of pharmacy

Dr.N.Damodharan Professor and head Department of pharmaceutics SRM college of pharmacy Suppositories are solid dosage forms intended for insertion into body orifices where they melt, soften, or dissolve